Research Article: Scrub Typhus Is an Under-recognized Cause of Acute Febrile Illness with Acute Kidney Injury in India

Date Published: January 30, 2014

Publisher: Public Library of Science

Author(s): Vivek Kumar, Vinod Kumar, Ashok K. Yadav, Sreenivasa Iyengar, Ashish Bhalla, Navneet Sharma, Ritesh Aggarwal, Sanjay Jain, Vivekanand Jha, Nicholas P. Day.

Abstract: BackgroundInfection-related acute kidney injury (AKI) is an important preventable cause of morbidity and mortality in the tropical region. The prevalence and outcome of kidney involvement, especially AKI, in scrub typhus is not known. We investigated all patients with undiagnosed fever and multisystem involvement for scrub typhus and present the pattern of renal involvement seen.MethodsFrom September 2011 to November 2012, blood samples of all the patients with unexplained acute febrile illness and/or varying organ involvement were evaluated for evidence of scrub typhus. A confirmed case of scrub typhus was defined as one with detectable Orientia tsutsugamushi deoxyribonucleic acid (DNA) in patient’s blood sample by nested polymerase chain reaction (PCR) targeting the gene encoding 56-kDa antigen and without any alternative etiological diagnosis. Renal involvement was defined by demonstration of abnormal urinalysis and/or reduced glomerular filtration rate. AKI was defined as per Kidney Disease: Improving Global Outcomes (KDIGO) definition.ResultsOut of 201 patients tested during this period, 49 were positive by nested PCR for scrub typhus. Mean age of study population was 34.1±14.4 (range 11–65) years. Majority were males and a seasonal trend was evident with most cases following the rainy season. Overall, renal abnormalities were seen in 82% patients, 53% of patients had AKI (stage 1, 2 and 3 in 10%, 8% and 35%, respectively). The urinalysis was abnormal in 61%, with dipstick positive albuminuria (55%) and microscopic hematuria (16%) being most common. Acute respiratory distress syndrome (ARDS) and shock were seen in 57% and 16% of patients, respectively. Hyperbilirubinemia was associated with AKI (p = 0.013). A total of 8 patients (including three with dialysis dependent AKI) expired whereas rest all made uneventful recovery. Jaundice, oliguria, ARDS and AKI were associated with mortality. However, after multivariate analysis, only oliguric AKI remained a significant predictor of mortality (p = 0.002).ConclusionsScrub typhus was diagnosed in 24% of patients presenting with unexplained febrile illness according to a strict case definition not previously used in this region. Renal abnormalities were seen in almost 82% of all patients with evidence of AKI in 53%. Our finding is contrary to current perception that scrub typhus rarely causes renal dysfunction. We suggest that all patients with unexplained febrile illness be investigated for scrub typhus and AKI looked for in scrub typhus patients.

Partial Text: Infections are responsible for a substantial portion of community acquired acute kidney injury (AKI) in India. The commonly implicated conditions include malaria, leptospirosis, dengue, enteric fever, viral and bacterial infections. Despite being endemic in Asia with an estimated one million cases occurring annually, scrub typhus, caused by the rickettsia Orientia tsutsugamushi, is highly underdiagnosed and under-reported cause of hospitalization [1], [2]. World Health Organization (WHO) identifies scrub typhus as a re-emerging disease in South-East Asia and the South-Western Pacific region with a case fatality rate of up to 30% in untreated cases and stresses the need for its surveillance [1]. Scrub typhus has been reported from various parts of India [3]–[8], and has recently been identified as one of the important neglected zoonoses of public health importance [9].

Out of 201 patients with fever and multisystem involvement seen during this period, 49 tested positive for O. tsutsugamushi DNA. None of these had any alternative diagnosis (Table 1). Amongst 152 patients who were negative for scrub typhus by aforementioned PCR, 20% patients had an alternative diagnosis (Table 2). Importantly, a total of 105 patients were recorded as positive for scrub typhus IgM ELISA. These included 43% of scrub typhus PCR negative patients. A total of 23% of patients within this subset (scrub typhus PCR negative but IgM ELISA positive) were assigned an alternative diagnosis. A comparison of the clinical features and laboratory abnormalities in scrub typhus positive and negative patients is given in Table 1. Vomiting, altered sensorium, bodyaches, tachycardia, hepatomegaly, lymphadenopathy, AKI and thrombocytopenia were significantly more common in patients with scrub typhus (Table 1).

This is the first report to comprehensively document the clinical picture, investigative profile, pattern of renal involvement and outcome in a cohort of patients of scrub typhus using a strict case definition. We show that scrub typhus is responsible for about 24% of all patients presenting with unexplained febrile illness and/or multi-system involvement. We also show that the renal involvement is fairly common in scrub typhus. AKI is seen in over 50% cases, and is an important predictor of mortality.